Without limiting the scope of the invention, its background is described in connection with carbapenem compounds having substitutions at the 5 position, the 6 position or both the 5 and 6 position of the basic nucleus of the 7-oxo-1-azabicyclo[3,2,0]hept-2-ene carbapenem compound.
An important mechanism of microbial resistance to β-lactam antibiotics is the bacterial production of enzymes that hydrolytically destroy β-lactam antibiotics, e.g., β-lactamases which include penicillins and cephalosporins. The resistance to β-lactam antibiotics can be transferred by plasmids that are capable of rapidly spreading the resistance to other members of the same strain and even other species. As a result of this transfer process, a patient can become infected with multiple organisms each resistance to β-lactam antibiotics. Based on the amino acid sequence β-lactamase enzymes have been organized into four molecular classes: Class A (preferentially hydrolyze penicillins), Class B (metalloenzymes), Class C (chromosomal cephalosporinases) and Class D (exhibit a unique substrate profile).
One strategy for overcoming this bacterial resistance is the use of β-lactamases inhibitors which are commonly administered in conjunction with an antibiotic since β-lactamase inhibitors do not possess antibiotic activity themselves. Current commercial inhibitors historically target only the clinically relevant class A β-lactamases; however, there has been an increase in the number of infections possessing class B, C, and D β-lactamases.
U.S. Patent Application Publication No. 2007/0265242, entitled, “Novel Carbapenem Compound,” discloses a carbapenem compound represented by the following formula
wherein R1 is C1 to C3 alkyl or C1 to C3 alkyl substituted by hydroxy. R is hydrogen atom or a group which regenerates a carboxyl group by hydrolysis in a living body, A is the following formula
wherein E is a 5 to 7 membered cyclic ring optionally containing 1 to 3 hetero atoms (excluding benzene ring) which forms a bicyclic ring in cooperation with the benzene ring, Y is hydrogen atom, C1 to C4 alkyl, C1 to C4 alkoxy, trifluoromethoxy, halogen atom or cyano group, or its pharmaceutically acceptable salt.
U.S. Pat. No. 7,022,691, entitled, “Inhibitors of Serine and Metallo-β-Lactamases” discloses compounds of the following formula:
useful for inhibiting simultaneously serine and metallo-β-lactamases enzymes, for enhancing the activity of β-lactam antibiotics, and for treating β-lactam resistant bacterial infections in a mammal.
U.S. Pat. No. 6,770,759, entitled, “Penicillanic Acid Derivative Compounds and Methods of Making,” discloses carbapenem compounds which have been developed and commercialized are poor in absorbability from the digestive tract, and; therefore, they are clinically used only in the form of injection, mainly intravenous injection. However, in the clinical field, it is desirable to select several administration routes from the viewpoint of circumstances or wishes of a patient, a therapeutic object, etc. Especially, oral administration of an antibacterial agent is easy and convenient for administration to a patient in comparison with injection. In view of the care of a patient at home, oral administration of the antibacterial agent is more convenient and the clinical usability is extremely high. It has been strongly desired in the clinical field to develop a carbapenem compound which has a potent antibacterial activity especially against Haemophilus influenzae (which widely gains resistance to the inhibitory effect of existing β-lactam agents together with mutation of penicillin binding proteins, such as β-lactamase, non-producing ampicillin resistant Haemophilus influenzae, and penicillin resistant Streptococcus pneumonia. All of them have a structural property having 1 β-methyl group and a side chain via sulfide bond which are said to contribute to an increase of chemical stability and biological stability, and are modified to a prodrug for increase of oral absorbability.
On the other hand, carbapenem compounds having an aryl ring via C—C bond as a side chain structure were known since 1980s (see e.g., U.S. Pat. Nos. 4,543,257, 4,775,669, and 5,258,509, Tetrahedron, 1983, Vol. 39, p 2531-2549, and Journal of Medicinal Chemistry, 1987, Vol. 30, p 871-880). However, these reports are concerned only to studies and developments on injections.
Although International Publication Nos. WO 02/053566, WO 03/040146 and WO 03/089431 relate to agents for oral administration, the substituent at position 3 of 7-oxo-1-azabicyclo[3.2.0]hept-2-ene which is a basic nucleus of the carbapenem compound is limited to a monocyclic ring such as benzene, thiophene or pyridine ring. As the substituent at position 3, carbapenem compounds having only naphthalene ring (as bicyclic ring wherein benzene ring fused with another cyclic ring) are known (U.S. Pat. Nos. 5,006,519 and 5,032,587, European Patent Nos. EP 466253B and EP 466254B), but other substituents on said position 3 are not referred to therein and such compounds are not applied for oral administration.
Therefore, carbapenem derivatives having substituents at various locations are known; however, carbapenem derivatives having substituents at the 5 and/or 6 position of the carbapenem core compound have not been reported.